The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

CHAPTER 8
The Search for How Mutant mtDNA
Is Amplified
This gap in the mitochondrial free radical theory was a particularly inviting challenge to a
newcomer in the field. Superficially, it seemed that all the information was available to
lead rapidly to a detailed mechanism for how mutant mitochondria out-competed wild-type
ones; but in fact, only a few possibilities had been proposed, all of which had serious difficulties.
8.1. Does Deleted—Shorter—mtDNA Replicate Faster?
An early suggestion 1 was that the mitochondria which were amplified were specifically
those that had suffered a large deletion in their DNA. The idea was that, having less DNA to
replicate, they could get it done more quickly and so out-replicate the normal mitochondria.
Such mutations had been found, 2 and it was clear that they take over cells. Unfortunately,
we now know that many point mutations are also amplified, 3 so this cannot be the whole
story. Moreover, it has since been established 4 that some mtDNA duplications are amplified:
thus, any selection there may be for small molecules must be easily overridden by some
other factor. Also, the tiny size of the mtDNA molecule means that, on average, it need be
replicated only at a rate of under ten base pairs per hour in order to keep up with the observed
rate of mitochondrial turnover. This is so hugely slower than the typical DNA replication
rate of about 2000 bases per minute 5 that it is hard to imagine mtDNA replication being
rate-limiting. In fact, replication of the whole molecule takes 1-2 hours. 10
A variant on this model 6 avoids this problem, but has one of its own. It was proposed
that certain parts of the mtDNA molecule act as inhibitors of mtDNA replication, only
allowing replication to proceed when more mitochondria are needed. These sequences were
hypothesised to be deleted or otherwise inactivated in mutant mtDNA, so that such molecules
engaged in runaway replication. This proposal faces the major difficulty that no such
cis-regulatory sequence has been identified, and that its existence becomes progressively
less plausible with every new mutation that is found to accumulate in vivo.
8.2. Do Perinuclear Mitochondria Trigger Their Own Replication?
A highly ingenious idea 7 was inspired by the discovery 8 that the cell does not replicate
all its mitochondria at once. Nor is replication a constant process, however: the truth seems
to be somewhere between. Mitochondria are replicated in pulses: a few percent of them are
replicated simultaneously, then none for a while. This allows the possibility that the signal
which tells the cell to replicate some mitochondria is somehow biased towards the replication
of mutant ones. We do not know what this signal is, but a perfectly plausible candidate is a
simple shortage of ATP in the nucleus. This may preferentially occur when there are
(randomly) a lot of mutant mitochondria around the nucleus. Now, if the replication signal
goes out from the nucleus and only gets to a few percent of the mitochondria in the cell,
then the beneficiaries are most likely to be exactly the ones near the nucleus, namely the
The Mitochondrial Free Radical Theory of Aging, by Aubrey D.N.J. de Grey.
©1999 R.G. Landes Company.